KR100537863B1 - Bioadhesive Tablet - Google Patents

Abstract

The present invention relates to a bioadhesive tablet present in a multi-layered form, wherein the tablet comprises at least one bioadhesive layer containing a total charge of a bioadhesive material, and which can be compressed directly during the manufacture of the tablet, and At least one layer containing the total content of the components.

Description

Bioadhesive tablets

The present invention relates to tablets having bioadhesive properties, which tablets can be used by transmucosal as well as nonmucosal routes depending on their structure.

Transmucosal administration has the advantage of improving clinical efficacy by reducing the dose by avoiding substantial metabolism of the active ingredient by the first-pass effect of the liver at the metabolic level. The active ingredient suffers from various enzymatic or chemical degradation processes along the gastrointestinal tract and disadvantages related to the organoleptic and physiological functions of the gastrointestinal tract.

Various properties desired for such tablets, such as improving the bioavailability of the active ingredient by controlling the release rate and the direction of flow of the active ingredient, or improving the adhesiveness of the tablet to tissues or mucous membranes To this end, a number of agents have been proposed.

In these formulations, the bioadhesive compound tends to be used in admixture with the active ingredient and other excipients (eg, swelling agents). By the way, the properties of these products are not sufficiently advantageously used. In practice, some bioadhesive compounds are trapped in the mixture and are not used for adhesion. Similarly, controlling the release rate of the active ingredient may prove difficult because not all of the active ingredient is always used.

In other formulations, it is necessary to use an adjuvant such as gelatin to achieve the desired effect with the choices made in the case of bioadhesive products.

In general, such currently available bioadhesive tablets have several types of limitations, for example insufficient bioadhesion, excessive bulkness, poorly aggregated structure in use, or the intensity of the active ingredient (s). ) And / or poor control of the flow direction.

Bioadhesive products have several problems due to sticking and are therefore difficult to use industrially. Because of the hydrophilic nature, bioadhesive products are difficult to treat by wet granulation when mixed with powders that tend to exhibit poor flow and treated as mixtures. In conclusion, these products are not very suitable for compaction.

It has now been found by the inventors to select specific forms of bioadhesive compounds and excipients, thereby making it possible to produce new types of tablets having a series of layers with different functions, and to prepare one or more layers of these layers. To work by direct compression.

Therefore, it is an object of the present invention to provide a novel optimal tablet in terms of low cost, adhesion and diffusion of the active ingredient contained therein and the efficacy of the active ingredient thereby.

In particular, it is an object of the present invention to provide tablets which can be used by the transmucosal or non-mucosal route and which are orally administered as necessary.

Tablets of the invention have a multi-layered form,

Can be pressed directly during the manufacture of tablets and adhered to biological tissues or mucous membranes by impregnation with water or biological body fluids present in the environment of biological tissues or mucous membranes, while at the same time providing for release of the active ingredient At least one bioadhesive layer containing a total content of bioadhesive material; And

At least one layer containing most of the total content of the active ingredient

Characterized in that it comprises a.

The bioadhesive layer (s) can be pressed directly, which represents a technical advantage compared to the preparation of bioadhesive tablets available to date, and it is observed that they can be made at lower cost.

In addition, the total content of the active ingredient and the total content of the engraftment adhesive substance are each present in separate layers. Thus, each layer can be prepared using the minimum amount of product required for a given effect. This provides the patient with economic benefits and benefits both in medical terms and in terms of patient comfort. Due to the concentration of the bioadhesive polymer in contact with the tissue or mucosa to which the tablet is applied, a strong bioadhesive effect and regenerative release control of the active ingredient are achieved.

The optimization of bioadhesion of the tablets of the present invention, when compared to the tablets of the prior art, allows for tablets with improved efficacy and longer long-term bioadhesion for the same or lower amounts of bioadhesive compounds. To manufacture. This advantage is particularly beneficial when the active ingredient is administered over a long period of time.

According to an advantageous arrangement, the tablets of the invention are also characterized in that they contain at least one layer which forms a blocker against the diffusion of the active ingredient and the penetration of water or the biological body fluid.

Therefore, such tablets not only induce the diffusion direction of the active ingredient, but also protect the tablet from erosion due to the movement of adjacent tissues (e.g., the upper lip when the tablet is buccally administered) and prevent inadequate stickiness of the tablet. This has the advantage of limiting the collapse of the matrix.

According to an advantageous embodiment, the bioadhesive layer of the tablet of the invention is a bioadhesive material, at least one swelling agent that is insoluble in the presence of biological fluids or swelling agent that is poorly soluble, and / or swelling agent or soluble in the presence of biological fluids. A gelling agent, and a mixture of one or more excipients and / or adjuvants that act as water-soluble or hydrophilic properties agents that can improve bioadhesion if necessary.

Bioadhesive materials are advantageously based on polymers modified with maleic anhydride or with derivatives such as pharmaceutically acceptable acids, esters or salts.

The bioadhesive material is preferably a copolymer of methyl vinyl ether and maleic anhydride.

In the context of the present invention, when carrying out the manufacture of the multilayered structure, such polymers are actually used intact as bioadhesives, without mixing and / or performing specific treatment with other bioadhesives as in the prior art.

Examples of such types of copolymers currently available on the market are those marketed under the trade name Gantrez® (GAF product).

The products include Gantrez® AN (anhydride form), S (acid form), ES (ester form) and MS (sodium and calcium salts).

Insoluble swelling agents or poorly swelling swelling agents in the presence of biological fluids, a group consisting of cellulose ethers such as sodium carboxymethylcellulose, cross-linked hydroxypropylcellulose and high molecular weight hydroxypropylcellulose, enteric and insoluble ( non-enteric) cellulose esters, groups of modified starches such as carboxymethyl starch and copolymers of divinylbenzene / potassium methacrylate, groups of methacrylic acid derivatives such as polymethylmethacrylate, crospovidone / cross Group consisting of polyvidone and high molecular weight polyvinyl alcohol, group consisting of alginic acid and derivatives thereof, group consisting of acrylic acid derivatives such as acrylic acid crosslinked with divinyl glycol and calcium salts thereof, carrageenans and derivatives thereof And copolymers of vinyl acetate and crotonic acid. It is advantageous to select from the group true.

Suitable swelling agents or soluble gelling agents in the presence of biological body fluids which are suitable for practicing the present invention include the group consisting of cellulose ethers such as methylcellulose, sodium carboxymethylcellulose and low molecular weight hydroxypropylmethylcellulose, enteric and non enteric Cellulose esters, low molecular weight polyvinyl alcohols, medium viscosity polyvinyl alcohols and polyoxyethylene glycols, povidone / polyvidone / copolyvidones, scleroglucanes and starch and modified starches ( For example, the group consisting of pregelatinized starch), the group consisting of carrageenan and derivatives thereof, and the group consisting of alginic acid and derivatives thereof.

Other excipients used in admixture with bioadhesive materials may improve bioadhesion, such as guar gum, xanthan gum, carob, carrageenate, pectin, alone or in biological or synthetic origin. Biological or synthetic proteins used in admixture with other proteins, cyclodextrins or betacyclodextrins, hydroxypropylbetacyclodextrins, derivatives such as some methylated betacyclodextrins, acrylic acid crosslinked with divinyl glycol and calcium salts thereof Acrylic acid derivatives, such as these, are mentioned.

Adjuvants that are water-soluble or act as medicaments with hydrophilic properties are excipients of the hydrocellulose group such as lactose, mannitol, colloidal silicon dioxide, microcrystalline cellulose, excipients of the gelatin, cellulose ether group, polyethylene glycol (PEG), polyoxamers And pyrrolidone.

The bioadhesive layer can be used in combination with bioadhesive materials 5% to 100%, insoluble swelling agents or poorly soluble swelling agents 0% to 80%, soluble swelling agents or soluble gelling agents 0% to 50%, bioadhesive polymers It is advantageous to contain 0% to 50% of an excipient which makes it possible to improve adhesion, and 0% to 80% of a water soluble adjuvant which acts as a medicament with hydrophilic properties.

As already emphasized, the preparation of such an adhesive layer makes it possible to limit the "sticking" phenomenon of the tablet to tissues other than the tissue intended for application of the tablet. In practice, the presence of the bioadhesive polymer is limited to the surface in contact with the mucosa or tissue. In the case of buccal adhesive tablets, the presence of an adhesive layer greatly facilitates the placing of the tablets and limits the displacement of the tablets on gums and lips during the initial stage of application, which improves bioadhesion and Finally increase patient comfort. This improvement means that the conventional risk of oral ingestion of buccal adhesive tablets due to poor bioadhesion during the initial stage of application is greatly reduced.

In the adhesive layer, fatty bodies may be added at a rate of 0% to 50% of the total mass of the layer for pharmaceutical manufacturing techniques. It is clear that this type of excipient with hydrophilic properties is likely to affect the diffusion profile of the active ingredient through the adhesive layer.

In a layer having most of the content of the active ingredient, hereinafter referred to as the main layer, this layer contains the presence of the active ingredient (s), at least one swelling agent or sparingly soluble swelling agent and / or biological body fluid in the presence of the biological body fluid. At least one swelling agent or soluble gelling agent which is soluble under one or more excipients which enable to obtain clathrates of the active ingredient if necessary and / or at least one excipient which acts as a medicament with water-soluble or hydrophilic properties, or It is advantageous to contain mixtures of one or more excipients which act as agents which are insoluble in water or have hydrophobic properties.

The medicaments already mentioned with respect to the adhesive layer are preferably selected from the respective products described above for each type of medicament.

Excipients that allow inclusion of the active ingredient include, for example, cyclodextrins or betacyclodextrins, hydroxypropylbetacyclodextrins, derivatives such as some methylated betacyclodextrins and glycerides such as glyceryl monooleate. Can be mentioned.

Adjuvants that act as insoluble or hydrophobic agents are specifically hydrogenated castor oil, magnesium stearate, natural and synthetic oils, natural or semisynthetic waxes, fatty acid esters and polyoxyethylene esters, fatty acids and fatty acid esters (monoglycer) Lides and triglycerides) and derivatives thereof such as polyethoxylated fatty acids (PEG stearate, ...), fatty alcohols and fatty alcohol esters and derivatives thereof such as polyethoxylated fatty alcohols (Octyldodeces-25, ...) and polyvinyl chloride.

The active ingredient (s) specifically include antihistamines, anticholinergic agents, mineral elements, allergens, topical or systemic anesthetics, antipyretics, nonnarcotic analgesics, narcotic analgesics, anticholinergic and non-cholinergic anticonvulsants, nonsteroidal antiinflammatory agents ( For example, thiaprofenic acid, indomethacin, diclofenac, ibuprofen, ketoprofen, naproxen, pyrocampam), steroidal anti-inflammatory agents (e.g. betamethasone, prednisolone), cytotoxins, anti-hormones Agents, anti-anemia, anti-nausea, anti-attentive, antihypertensive, beta-blockers (e.g., propanolol, atenool, metoprolol), convertase inhibitors (e.g., catopril, enalapril), angiotensin Antagonists, calcium antagonists (e.g. nifedipine and diltiazem), central action hypotensives, vasodilators, hypolipidemia, oral antidiabetics, anticoagulants, antiplatelet drugs , Calcium antagonists, nitrate derivatives used in the treatment of coronary artery insufficiency, non-nitrate antianginal agents, diuretics, derivatives of digitalin and similar products, antiarrhythmic agents, antihypertensive circulatory tonics, vasodilators, anti-angiogenic agents, vascular protective agents And intravenous tonics, hormones, anti-herpes, anti-sensitizers, anti-ulcer drugs (eg ranitidine, cimetidine), antacids, laxatives, anti-diarrheals, antifungals, gallstones, interferons, enzymes, anticonvulsants, antibacterials, preservatives , Anti-herpes, uterorelaxants, uterine contractors, estrogens, progestogens, estroprogestogens, active ingredients used for lactation (e.g. bromocriptine), for the treatment of infertility Active ingredients, antigonadotropins, anticoagulants, thrombolytics, antifibrin solubilizers, vitamins, hemostatics, cyclosporin, alkylating agents, antibiotics, antiviral agents, antiparasitic agents, vaccines, diagnostic products, Active ingredients used in the treatment of pancreas, appetite enhancers, active ingredients used in the correction of metabolic abnormalities, active ingredients used in the nutrition of the mouth or intestines, anticonvulsants, anti-Parkin's drugs, antimyopathy, Alzheimer's disease Active ingredients, antimigraine, neuroleptics, anxiolytics, hypnotics, sedatives, antidepressants, normothymic, psychostimulants, dependence of alcoholism, active ingredients used in tobacco detoxification and drug detoxification Glaucoma, Shandong, Tracheal dilator, Anti-asthma, Anti-acupuncture, Bronchial expectorant, (local) anti-induced stimulant, Active ingredient used to treat osteopathy, Active ingredient used to treat acute seizures of gout, Decreased urine Active ingredients used in the treatment of pain, dyspareunia, muscle relaxants, active ingredients used in the treatment of osteoarthritis, salivary insufficiency correcting agents, pears Is selected from the active ingredients employed in the gyeolseokjeung treatment, the active ingredients employed in the renal failure treatment, the active ingredients employed in the bed-wetting treatment, the active ingredient used in the treatment of degenerative ejaculation, erectile dysfunction, such as an active ingredient for the treatment.

Molecules contained in the composition according to the invention include, but are not limited to, contrast agents, radioactive elements, minerals and colorants.

The main layer is obtained from 70% to 100% of the total content of the active ingredient of the tablet, 0% to 50% of insoluble swelling agent or poorly soluble swelling agent, 0% to 50% of soluble swelling agent or soluble gelling agent, and inclusions of the active ingredient It is advantageous to contain 0% to 50% of the excipient which makes it possible, 0% to 50% of the water-soluble adjuvant acting as a medicament with hydrophilic properties, and 0% to 50% of the water-insoluble adjuvant acting as a medicament with hydrophobic properties.

As noted above, the multilayer tablet provided by the present invention contains at least one blocking layer.

The barrier layer (s) are soluble in the presence of an amount of active ingredient that may range from 0 to 30% of the total content, at least one swelling agent or insoluble swelling agent and / or biological body fluid insoluble in the presence of biological body fluids. Phosphorus swelling agent or soluble gelling agent, and if necessary, one or more excipients to obtain an inclusion of the active ingredient, and / or adjuvant and / or water insoluble or hydrophobic properties acting as a medicament with water soluble or hydrophilic properties. It is prepared predominantly from one or more agents which act as medicaments.

These various reagents are advantageously selected from the compounds given above for each type.

The barrier layer can provide 0% to 30% of the total active ingredient content of the tablet, 0% to 80% of insoluble swelling agent or poorly soluble swelling agent, 0% to 80% of soluble swelling agent or soluble gelling agent, and inclusions of the active ingredient. It is advantageous to contain 0% to 50% excipient, 0% to 25% adjuvant acting as a water-soluble or hydrophilic agent, and 0% to 50% adjuvant acting as a water-insoluble or hydrophobic agent. .

In addition, the three types of layers include other excipients or materials selected from the agents listed below, if necessary:

Diluents, for example of lactose and derivatives thereof or of mixed products such as dicalcium dihydrogen phosphate, microcrystalline cellulose and combinations thereof (for example, microcrystalline cellulose and colloidal silicon dioxide (Prosolv SMCC purchased from Mendel) Mixtures), starch and derivatives thereof (eg, pregelatinized starch);

Binders, for example povidone and polyvidone, ethylcellulose, alginic acid and derivatives thereof, maltodextrin, anhydrous or modified crystalline lactose monohydrate or mixtures thereof (for example prepared from lactose and microcrystalline cellulose) Mixed product (eg, a combination of microcrystalline cellulose and colloidal silicon dioxide (Prosolv SMCC) purchased from Mendell), some substituted hydroxypropylcellulose, starch and Derivatives thereof (eg, pregelatinized starch), talc;

Glidants, for example magnesium stearate, esters of fatty alcohols, esters of fatty acids, sodium stearyl fumarate, hydrogenated vegetable oils, derivatives of polyethylene glycol;

Modified starches such as flow enhancers, colloidal silicon dioxide, pregelatinized starch;

Aroma blockers, for example certain derivatives of methacrylic acid;

To monitor the development of the tablet in situ to avoid the formation of agents related to the agglomeration of the tablet and to maintain its overall appearance, i.e. excipients or the formation of, for example, cleavage, hole formation, non-uniform swelling between the various layers of the tablet. Substance that makes it possible.

The layers may also incorporate those listed below:

Absorption enhancers;

Solubilizers, for example polysorbates, pyrrolidones, derivatives of polyethylene glycol, derivatives of propylene glycol and glycerol, derivatives of polyethylene glycol (for example glycerol polyethylene glycol hydroxystearate);

- air freshener;

Colorants;

Sweeteners;

Plasticizers;

Antioxidants;

Disintegrants, for example sodium croscarmellose, sodium carboxymethyl starch, some substituted hydroxypropylcellulose, crospovidone, sodium starch glycolate;

Laminating agents, coatings, film formers, for example hydroxypropylcellulose, methacrylic acid derivatives, copolymers of vinyl acetate and crotonic acid;

Medicaments contained in the compositions of gloss and gloss enhancing liquids;

-Agents that protect the active ingredient from heat, such as sucrose derivatives.

These various layers that make up a tablet may contain coated or uncoated microcapsules or nanoparticles or nanogranules or nanocapsules.

The tablets of the present invention may have specific structures (relative arrangement of layers) that allow to direct the flow direction of the active ingredient to the desired route of administration (s).

The compound (s) present in the adhesive layer (apart from the native bioadhesive compound) may be the same or different from the compound (s) present in the main layer of the tablet. It is preferred that the compound (s) of the adhesive layer are medium viscosity or high viscosity hydroxypropylmethylcellulose (s) (HPMC), for example Metocel K 15M and K 100M P (color cone). Advantageously, such excipients are associated with bioadhesive phenomena because the excipients can form hydrogels, and the hydrogels swell gently, thereby improving long term bioadhesion.

If short-term adhesion is desired, the low viscosity hydroxypropylmethylcellulose or corn starch or any other excipient is selected from the monitored compounds in the composition of the adhesive layer.

In order to obtain a gentle and sustained release of the active ingredient, it is desirable to select the same excipient (s) which ensures controlled release for the main and adhesive layers of the tablet, provided that the selected compound is combined with a bioadhesive polymer. At this time, it should be possible to obtain a bioadhesion corresponding to a predetermined application time.

If the aim is to obtain a fast release profile (highest in plasma) of the active ingredient and to carry out prolonged and sustained release of the active ingredient, the non-bioadhesive excipient (s) present in the adhesive layer may rapidly form the hydrogel. It should be chosen for its performance and compatibility with bioadhesive polymers. The non-bioadhesive compound (s) that make up the main layer of the tablet should be selected to enhance the release of the active ingredient by the oral route with one or more phenomena such as enhanced diffusion (porosity), disintegration and the like.

Fast release profiles or slow release profiles can also be obtained by mixing or not mixing the non-bioadhesive excipient (s) using specific pharmaceutical manufacturing techniques for preparing the layers.

The fast release profile is obtained by a direct compression process and the slow release profile is preferably obtained by the wet granulation process of the main layer and / or barrier layer.

Preferred tablets containing one or more barrier layers are predominantly three-layer tablets made for use by transmucosal routes, wherein the inner active ingredient layer is respectively covered with a bioadhesive layer and a barrier layer on both opposing surfaces, It is covered with a bioadhesive layer or barrier layer on the side, or covered with a bioadhesive layer on both surfaces, and covered with a barrier layer on the side.

As a variant, the tablets of the present invention are prepared primarily for use by a non-mucosal route and are formed continuously from an outer bioadhesive layer, a blocking layer, an active ingredient layer, the layers overlapping or, if necessary, the active ingredient layer It is covered with a blocking layer on at least one side or with an outer blocking layer on its surface.

According to another variant, the tablets of the present invention are prepared for use by predominantly complex routes, ie transmucosal or non-mucosal routes, comprising a bioadhesive layer, an active ingredient layer and a barrier layer, the layers overlapping A barrier layer overlaps on one or both sides of the active ingredient layer or opposite two outer bioadhesive layers overlap the inner barrier layer and the inner active ingredient layer.

Observation of a very suitable dimension in terms of application shows that the butterfly is about 2 mm to 30 mm and the thickness is about 1 mm to 5 mm.

In general, as defined above, tablets may be flat, semi-convex, rectangular, equilateral tetrahedral, and may exhibit a format or any geometry that is rounded or not rounded. It has the advantage of keeping the tablet as long as possible for a long time. The tablet is divisible. The tablet may be perforated.

The tablet may include coated or uncoated microgranules, microcapsules, nanoparticles or nanocapsules.

The novel tablets according to the invention have medicinal, therapeutic or prophylactic or health uses in humans or animals. These new tablets may be used for oral administration, lingual administration, administration through the buccal mucosa (the larynx or gums), vaginal, anal, nasal, rectal, or through the gastrointestinal tract, or on the internal organs by surgery. It is advantageous. Depending on their structure, the release of the active ingredient may or may not occur systemically. It should be noted that small dimension pharmaceutical forms are suitable for ophthalmic use on the conjunctiva of the eye, especially on the conjunctival sac and cornea.

In addition, tablets can be used as a bioadhesive support constructed by therapeutic or health methods by their bioadhesive properties. For example, tablets may be loaded with compounds that can generate a localized magnetic field (due to bioadhesion). This magnetic field, when active, allows for the action of the second pharmaceutical form and the localized release of the substance at one time in one position.

The invention also relates to a process for the preparation of the tablets as defined above.

The method,

Directly compressing the mixture of prepared components to form a bioadhesive layer, and

Directly compressing the mixture of the prepared ingredients to form an active ingredient layer and / or directly compressing the mixture of the prepared ingredients to form a barrier layer, or the mixtures obtained by wet granulation or dry granulation Pressing all or both of the mixtures

Characterized in that it comprises a.

Other features and advantages of the invention are illustrated with reference to FIGS. 1 to 3 in the following examples.

Example 1

a) preparation of the mixture used to form the various layers

Mixture A used to form the active ingredient layer or the main layer:

The excipient components in the table below were weighed to produce the equivalent of 100 major layers.

Melatonin, dicalcium dihydrogen phosphate and 1/2 amount of ethylcellulose were mixed for 10 minutes in a Turbula. This mixture was partitioned through a 0.8 mm sieve. The remaining amount of ethylcellulose was dissolved in 5 ml of ethanol. The mixture was granulated with an alcohol solution of ethylcellulose at 10 minutes for 10 minutes using Kitchen Aid. The material obtained was assayed with a 0.8 mm sieve. After drying, the granules were sifted (eyes: 0.4 mm). The obtained granules were mixed with hydroxypropylmethylcellulose. Magnesium stearate was then added and the mixture was homogenized.

Mixture B used to form the bioadhesive layer:

The excipients in the table below were weighed to make the equivalent of 100 bioadhesive layers.

The product can be mixed directly before pressing.

The copolymer of methylvinylether and maleic anhydride was mixed with hydroxypropylmethylcellulose in a Turbula for 10 minutes. Magnesium stearate, colloidal silicon dioxide and yellow iron oxide were added and the mixture was mixed for 4 minutes in a mixer (Turbula) as a whole.

Mixture C used to form the barrier layer:

The excipients in the table below were weighed to produce the equivalent of 100 barrier layers.

The amount of ethylcellulose was divided into two equal fractions. The first fraction was mixed with all dicalcium phosphate in a Turbula for 10 minutes. The resulting mixture was partitioned through a 0.8 mm sieve. The remaining amount of ethylcellulose was dissolved in 5 ml of ethanol. The above mixture was granulated with an alcohol solution of ethylcellulose by setting the speed 2 for 10 minutes using chitin aid. The material was assayed with a 0.8 mm sieve. After drying, the granules were sifted (eyes: 0.4 mm). Hydroxypropylmethylcellulose was mixed with the granules. Magnesium stearate and red iron oxide were then added and the mixture was homogenized for 4 minutes in a Turbula.

b) pressing step

The compacting operation was performed manually on an EK0 type KORSH instead of the compacting machine to obtain flat and round tablets. The tablet had a thickness of 2 mm and a diameter of 10 mm.

Compression of 100 mg of mixture A corresponding to the main layer was carried out on a die having a diameter of 8 mm and a flat format. The obtained tablet was recovered. A die in 10 mm format was charged with 50 mg of mixture C and pressed lightly. Tablets in 8 mm diameter format were placed in the center of the compression chamber. The compression chamber was charged with the remaining 50 mg of the mixture C. The height of this mixture was equalized to the top height of the tablet and gently pressed. Subsequently, 100 mg of the mixture B was fed to this pressing chamber. The height of this mixture was equalized and final compression was performed. 300 mg of the final finished flat tablet was obtained. The tablet had a structure in which the bioadhesive layer 1 and the main layer 2 were covered by a barrier layer 3 on the side and surface of the tablet, as shown in FIG.

In addition, by working with mixture B in the first and final stages and placing only mixture C on the side according to the method as described above, 2 trapping the active ingredient layer 2 as shown in b of FIG. It was also possible to obtain a structure comprising two outer bioadhesive layers 1, the sides of which were covered by the barrier layer 3.

As a variant, tablets of the type as shown in c of FIG. 1 are compressed by filling a compression chamber with 50 mg of mixture B, followed by placing a previously prepared tablet using mixture A in the center of the die, It was then prepared by adding 50 mg of mixture B around the tablet and pressing to form a bioadhesive layer 1. Then mixture C was introduced into the hopper to form the barrier layer 3.

Tablets may be placed on the gum mucosa of the patient and may release melatonin in a controlled manner for 8 hours without disintegration, without detachment or adhesion in an inappropriate manner. According to this design, melatonin can be released primarily through the transmucosal route and active ingredients and excipients can be used in reduced amounts.

Example 2

a) Preparation of Mixtures A, B and C

To prepare Mixture A, the excipients in the table below were weighed to make the equivalent of 100 main layers.

Subsequently, the same procedure as in Example 1 was followed to mix, sieve, granulate, assay, dry and sift the excipients to obtain 0.4 mm granules.

Similarly, a bioadhesive layer (mixture B) and a barrier layer (mixture C) were prepared as described in Example 1. The excipients were the same, but because the amount of alcohol to be used for wet granulation was present, the amount of the excipients was bisected.

b) pressing step

The compaction operation was performed manually on the EK0 type KORSH instead of the compaction machine to obtain a circular flat tablet.

Mixture C was preliminarily pressed to form barrier layer 3.

Subsequently, the compression chamber was filled with the mixture A containing the active ingredient (pyroxycam). Preliminary compression forms the active ingredient layer 2 over the barrier layer.

The die was then provided with mixture B (bioadhesive layer) and the active ingredient layer placed thereon. The final compression resulted in a round flat tablet (about 8 mm in diameter) weighing about 150 mg.

The tablet had a structure in which layers (1), (2) and (3) were overlapped as shown in FIG.

It also contains a barrier layer on one side as shown in b of FIG. 2 and a barrier layer on each of the two sides of the main layer and not on its outer surface as shown in c of FIG. 2. I did not get a structure.

The b structure of FIG. 2 was obtained by placing a tablet prepared in advance using Mixture A (6 mm in diameter) on a die (relative to the edge of the compression chamber) in an offset manner.

The c structure of FIG. 2 was obtained by forming the barrier layer 3 on both sides according to the method described in Example 1 with respect to FIG. According to another variant, a structure such as shown in d of FIG. 2 was produced. The operation was performed as described for c in FIG. 2, but the barrier layer was replaced with a bioadhesive layer.

2E was obtained according to the method described for a in FIG. 2, but in this case the barrier layer was replaced with a bioadhesive layer. In addition, as another modification of FIG. 2E, the structure shown in FIG. 2F in which the bioadhesive layer, the main layer, the blocking layer, and another main layer is overlapped is obtained.

The tablet may then be placed on the gum mucosa of a patient with inflammatory rheumatic disease. Tablets were able to release pyroxycam in a controlled manner for 6 hours without deterioration.

Example 3

a) Preparation of Mixtures A, B and C

Mixtures A, B and C were prepared by treatment as described in Example 1, and mixture A was obtained from the excipients in the table below which were used in an amount capable of producing the equivalent of 100 main layers.

Similarly, a bioadhesive layer (mixture B) and a barrier layer (mixture C) were prepared as described in Example 1. The excipients were the same, but the amount of excipients was bisected because there was an amount of alcohol to be used for wet granulation.

b) pressing step

The compaction operation was performed manually on the compaction machine to obtain flat tablets in the form of parallelepipeds.

Mixture B was lightly pressed to form a layer (bioadhesive layer).

A portion of mixture C was placed on the adhesive layer. A barrier layer was formed on the bioadhesive layer by preliminary compression.

The tablets prepared beforehand using mixture A (betamethasone) were then placed in place. The tablet, 6 mm in diameter, was placed in the center of the compression chamber. The die was filled with mixture C to the upper height of the tablet. Tablets were completed by final compression.

A tablet weighing about 150 mg was obtained, which had a bioadhesive layer (1), a blocking layer (2) and a main layer (3) as shown in a of FIG. It has a structure.

In addition, by arranging tablets 6 mm in diameter prepared from the mixture A in an offset manner, a design as shown in FIG. 3B was also obtained.

In addition, as a variant, when the mixtures A, C and B are introduced and continuously compressed, the structure c of FIG. 3 or the mixture C further introduced to be used to prepare another blocking layer 3 is shown in FIG. d structure was also obtained.

The tablets can then be placed on the buccal mucosa of patients with aphthaic ulcers. The tablets were able to release betamethasone in a controlled manner for 4 hours without deterioration. This design mainly enabled parenteral mucosal release, ie by the local route.

This design allowed the rapid release of the active ingredient by the oral route and extended release through the mucosa. Therefore, according to such a tablet, it was possible to continuously release the active ingredient into the plasma for 2 hours from the reduced amount of the active ingredient. It may be advantageous to incorporate flavors or blockers to enhance patient comfort.

Tablets of the same type could be made, for example, using other active ingredients, vitamins, amino acids and hormones.

Example 4

a) Preparation of Mixtures A, B and C

Mixtures A and B were prepared by treatment as described in Example 1, except that for Mixture A, the excipients in the table below were used in the indicated amounts to produce the equivalent of 100 main layers.

To prepare mixture C, the equivalent of 100 barrier layers was prepared using the excipients in the table below.

Hydroxypropylcellulose was mixed with dicalcium phosphate for 10 minutes in a Turbula. The resulting mixture was sifted through a 0.8 mm sieve. All polyvinylpyrrolidone was dissolved in 3.5 ml of water. Using this solution, the mixture was granulated by setting the speed 2 for 8 minutes in the kitchen aid. The material was assayed with a sieve 0.8 mm. After drying, the granules were sifted using a 0.4 mm sieve. Hydroxypropylmethylcellulose was mixed with the granules for 10 minutes in a Turbula, then magnesium stearate and red iron oxide were added, and then the mixture was homogenized for 4 minutes in a Turbula.

b) pressing step

The compaction step was performed on EK0 type KORSH instead of the compaction machine to obtain round and flat tablets.

Round flat tablets with a diameter of 6 mm were obtained from mixture A (main layer).

The compression chamber was charged with 50 mg of mixture C. Preliminary compression was performed (blocking layer). The tablet obtained using mixture A was placed on the barrier layer at the center of the die. The die was then charged with 50 mg of mixture B to cover over the tablets forming the main layer containing the active ingredient (prochlorperazine). Final compaction was performed.

A round, flat tablet weighing about 150 mg and 8 mm in diameter was obtained, which had a design as shown in c of FIG. 1.

The tablets can then be placed in the oral mucosa of patients suffering from motion sickness and vomiting. Tablets were able to release prochlorperazine in a controlled manner for 5 hours without deterioration. This design allowed prolonged release mainly through the transmucosal pathway.

Example 5

a) Preparation of Mixtures A, B and C

Mixtures A and B were prepared by treatment as described in Example 1, except that for Mixture A, the excipients in the table below were used in the indicated amounts to produce the equivalent of 100 main layers.

Excipients except magnesium stearate were mixed in a Turbula for 10 minutes. The resulting mixture was sorted into 0.8 mm sieves. Magnesium stearate was then added and the mixture was mixed for 4 minutes in a Turbula.

To prepare mixture B, the equivalents of 100 bioadhesive layers were prepared by weighing the excipients in the table below.

To prepare mixture C, the equivalent of 100 barrier layers was prepared using the excipients in the table below.

Glyceryl monostearate was mixed with hydroxypropylcellulose for 5 minutes in a Turbula. The material was assayed with a sieve with a mesh size of 0.8 mm. Red iron oxide was added and the mixture was mixed for 4 minutes in a Turbula.

b) pressing step

Round and flat tablets were obtained by performing the compaction operation on EK0 type KORSH instead of the compaction machine.

Round flat tablets with a diameter of 6 mm were obtained from mixture A (main layer).

The compression chamber was charged with 50 mg of mixture C. Preliminary compression was performed (blocking layer). Tablets made using Mixture A were placed on top of the barrier layer at the center of the die. The die was then charged with 50 mg of mixture B to cover the tablets forming the main layer containing the active ingredient (nifedipine). Final compaction was performed.

A round flat tablet weighing about 150 mg was obtained, which had a design as shown in c of FIG. 1.

Tablets can be placed on the buccal mucosa of patients undergoing hypertension, replacing treatment by the sublingual route, where the tablets can release trinitrin in a controlled manner for 2 hours without deterioration. This design enabled the rapid release of the active ingredient by transmucosal pathway.

Example 6

a) Preparation of Mixtures A, B and C

Mixtures A and B were prepared by treatment as described in Example 5, except that for Mixture A, the subparifiers in the table below were used in the indicated amounts to produce equivalents of 20,000 main layers.

Excipients except magnesium stearate were mixed in a OURS type 10 liter planetary mixer at a rate of 35% for 10 minutes. The resulting mixture was sorted into 0.8 mm sieves. Magnesium stearate was then added and mixed at OURS for 35 minutes at a rate of 35%.

To prepare Mixture B, the equivalents of 20,000 bioadhesive layers were prepared by weighing the excipients in the table below.

The product was mixed directly before pressing.

Copolymers of methylvinylether and maleic anhydride were mixed in hydroxymethylcellulose and OURS type planetary mixers at a rate of 35% for 10 minutes. Magnesium stearate, colloidal silicon dioxide and yellow iron oxide were added and the entire mixture was mixed for 4 minutes in a OURS mixer.

To prepare mixture C, equivalents of 20,000 barrier layers were prepared using the excipients in the table below.

Glyceryl monostearate was mixed with hydroxypropylcellulose at a rate of 35% for 10 minutes in a OURS type planetary mixer. This mixture was assayed with a sieve 0.8 mm. Red iron oxide was added and mixed for 4 minutes in a OURS mixer.

b) pressing step

The compaction operation was performed on a multilayer machine (Manesti, Liverpool). The multi-layer machine has a flat format with a diameter of 8 mm.

The machine was adjusted to convey mixture C (blocking layer) on line 1, mixture A (main layer) on line 2, and mixture B (bioadhesive layer) on line 3. The machine was assayed to carry 50 mg of direct compression mixture per line. Final compaction force was 3,000 kg / cm ² . The compression rate was 20,000 tablets / hour.

A round, flat tablet weighing about 150 mg was obtained, which had a design as shown in a of FIG. 2.

Tablets could be placed on the buccal mucosa to adjust the sleep of shift workers. Tablets were able to release melatonin for 4 hours in a controlled manner without deterioration. According to this design, the active ingredient could be released rapidly through the parenteral mucosal route and melatonin could be released prolonged through the transmucosal route.

Example 7

a) Preparation of Mixtures A, B and C

Mixtures A and B were prepared by treatment as described in Example 6, except that for mixture A, the excipients in the table below were used in the indicated amounts to produce the equivalent of 10,000 main layers.

To prepare mixture B, the equivalents of 10,000 bioadhesive layers were prepared by weighing the excipients in the table below.

The product was mixed directly before pressing.

The copolymer of methylvinylether and maleic anhydride was mixed with hydroxypropylmethylcellulose in a Turbula for 10 minutes. Magnesium stearate, colloidal silicon dioxide and yellow iron oxide were added and the entire mixture was mixed for 4 minutes in a Turbula.

To prepare mixture C, the equivalent of 10,000 barrier layers was prepared using the following excipients.

Glyceryl monostearate was mixed with hydroxypropylcellulose in Turbula for 10 minutes. This mixture was assayed with a sieve 0.8 mm. Red iron oxide was added and the mixture was mixed for 4 minutes in a Turbula.

b) pressing step

The compaction operation was performed on a multilayer machine (Manesti, Liverpool). The multilayer machine has a flat format 3 mm in diameter and 1.0 mm thick.

The machine was adjusted to convey mixture C (blocking layer) on line 1, mixture A (main layer) on line 2, and mixture B (bioadhesive layer) on line 3. The machine was assayed to carry 10 mg of direct compression mixture per line. The final compressive force was 2,500 kg / cm ² . The compression rate was 10,000 tablets / hour.

A round, flat tablet weighing about 30 mg was obtained, which had a design as shown in a of FIG. 2.

Tablets may be placed in the conjunctival blind of the eye and release of thymolol via the parenteral mucosal route used to treat glaucoma. Tablets could prolong the active ingredient release in the same manner as conventional gels.

Thus, the present invention provides highly effective bioadhesive tablets with optimal flexibility of application.

The tablets of the present invention are particularly low in risk of and inadvertent desorption or overdose. Tablets of the present invention have the advantage of maintaining adhesion between the various layers and having a uniform distribution of stresses resulting from changes in the degree of hydration of the various layers. Therefore, the tablets of the present invention do not have the disadvantages associated with layer separation such as early release or overrelease of the active ingredient.

In addition, the tablet of the present invention does not cause discomfort due to volume, and does not cause discomfort due to allergy, sensitivity or irritation (of course, the effect of the active ingredient (s) alone is not considered).

1 a to c are views showing the relative arrangement of the layers mainly applicable to the transmucosal path.

2A to 2D illustrate the relative arrangement of layers applicable to the composite transmucosal / non-mucosa pathway.

3 a to d show the relative arrangement of layers that can be applied primarily to non-mucosal routes.

<Description of Symbols for Main Parts of Drawings>

One :

2 :

3:

Claims (25)

One or a plurality of living bodies having a direct compressed structure and containing a total content of a bioadhesive material based on a product selected from the group consisting of polymers modified by maleic anhydride and pharmaceutically acceptable derivatives thereof An adhesive layer, said bioadhesive layer that adheres upon action to biological tissues or mucosa by impregnation with water or biological body fluids present in the environment of biological tissues or mucosa and allows release of the active ingredient, and Bioadhesive tablets in the form of a multilayer comprising one or a plurality of layers (main layer) containing most of the total content of the active ingredient. A tablet according to claim 1, which also contains one or more barrier layers which form a barrier to the diffusion of the active ingredient and the penetration of water or biological fluids. The bioadhesive layer of claim 1 or 2, wherein the bioadhesive layer comprises one or more swelling agents or poorly swelling agents which are insoluble in the presence of a bioadhesive material, biological body fluid; Or swelling agents or gelling agents that are soluble in the presence of biological body fluids; Or a tablet characterized in that it contains a mixture of both. The tablet according to claim 1, wherein the bioadhesive material is mainly composed of a copolymer of methyl vinyl ether and maleic anhydride. The bioadhesive layer of claim 1, wherein the bioadhesive layer comprises 5% to 100% of a bioadhesive material, 0% to 80% of an insoluble swelling agent or a poorly soluble swelling agent, 0% to 50% of a soluble swelling agent or a soluble gelling agent, A tablet characterized in that it advantageously contains from 0% to 50% of an excipient which can be used in admixture with a bioadhesive polymer to improve bioadhesion, and from 0% to 80% of a water-soluble adjuvant acting as a medicament with hydrophilic properties. The method according to claim 1 or 2, wherein the main layer comprises one or more swelling agents or poorly swelling agents which are insoluble in the presence of the active ingredient (s), biological body fluids; Or one or more swelling agents or soluble gelling agents that are soluble in the presence of biological body fluids; Or a tablet characterized in that it advantageously contains a mixture of both. The method of claim 6, wherein the main layer comprises one or more excipients which enable to obtain inclusions of the active ingredient; Or one or more excipients which act as medicaments with water-soluble or hydrophilic properties; Or a tablet characterized in that it advantageously further contains a mixture of both. 8. The active layer of claim 7 wherein the main layer comprises 70% to 100% of the total active ingredient content of the tablet, 0% to 50% insoluble swelling agent or poorly soluble swelling agent, 0% to 50% of soluble swelling agent or soluble gelling agent, active Free from 0% to 50% excipients, 0% to 50% water soluble adjuvant acting as a medicament with hydrophilic properties, 0% to 50% water insoluble adjuvant acting as a medicament with hydrophobic properties Tablets characterized in that it contains. 3. The barrier layer of claim 2, wherein the barrier layer comprises active ingredients in a proportion that may range from 0% to 30% of the total content, one or more swelling agents or poorly swelling agents that are insoluble in the presence of biological fluids; Or swelling agents or gelling agents that are soluble in the presence of biological body fluids; Or tablets characterized in that they are mainly prepared from all of them. The method of claim 9, wherein the barrier layer further comprises one or more excipients to enable inclusion of the active ingredient inclusions; Or one or more adjuvants that act as medicaments that are water soluble or have hydrophilic properties; Or one to three selected from one or a plurality of drugs that act as drugs that are insoluble in water or have hydrophobic properties. The barrier layer of claim 10, wherein the barrier layer comprises 0% to 30% of the total active ingredient content of the tablet, 0 to 80% insoluble or poorly soluble swelling agent, 0% to 80% of a soluble swelling agent or soluble gelling agent, Advantageously containing 0% to 50% of excipients to obtain a complex, 0% to 25% of water soluble auxiliaries acting as medicaments with hydrophilic properties, 0% to 50% of insoluble auxiliaries acting as medicaments with hydrophobic properties Tablet characterized by. 4. The group according to claim 3, wherein the insoluble swelling agent or poorly swelling agent in the presence of biological body fluid is a group consisting of cellulose ethers such as sodium carboxymethylcellulose, crosslinked hydroxypropylcellulose and high molecular weight hydroxypropylcellulose, enteric) and non-enteric cellulose esters, modified starches such as carboxymethyl starch and copolymers of divinylbenzene / potassium methacrylate, methacrylic acid derivatives such as polymethylmethacrylate Group, group consisting of crospovidone / crosspolyvidone and high molecular weight polyvinyl alcohol, group consisting of alginic acid and derivatives thereof, group consisting of acrylic acid derivatives such as acrylic acid crosslinked with divinyl glycol and calcium salts thereof, carrageenan ( carrageenans) and derivatives thereof and vinyl acetate with crotonic acid Purification features an advantageously selected from the group consisting of a polymer. 4. A group according to claim 3 wherein suitable swelling agents or soluble gelling agents which are soluble in the presence of biological body fluids comprise cellulose ethers such as methylcellulose, sodium carboxymethylcellulose and low molecular weight hydroxypropylmethylcellulose. , A group consisting of enteric and non-enteric cellulose esters, low molecular weight polyvinyl alcohols, moderately polyvinyl alcohols and polyoxyethylene glycols, povidone / polyvidone / copolyvidone, scle A tablet characterized in that it is selected from the group consisting of modified starches such as scleroglucans, starch, and pregelatinized starch, the group consisting of carrageenan and derivatives thereof, the group consisting of alginic acid and derivatives thereof. The composition of claim 1, which is a three-layer tablet made primarily for use by the transmembrane pathway, wherein the inner active ingredient layer is covered with a bioadhesive layer and a barrier layer, respectively, on both opposing surfaces, the bioadhesive layer or A tablet characterized by being covered with a barrier layer or covered with a bioadhesive layer on both surfaces and a barrier layer on its side. 3. A tablet according to claim 1 or 2, which is prepared primarily for use by a non-mucosal route and is formed continuously from an outer bioadhesive layer, a blocking layer, an active ingredient layer, and these layers are superimposed. The tablet according to claim 15, wherein the active ingredient layer is covered with a barrier layer on one or more sides or with an outer barrier layer on its surface. The method according to claim 1 or 2, which is prepared for use by a complex route, i.e. a transmucosal or non-mucosal route, comprising one or a plurality of bioadhesive layers, an active ingredient layer and a blocking layer, which layers Overlapping, wherein the barrier layer is superimposed on one or both sides of the active ingredient layer or opposite two outer bioadhesive layers are superimposed with the inner barrier layer and the inner active ingredient layer. The tablet according to claim 1 or 2, wherein the butterfly is between 2 mm and 30 mm and the thickness is between 1 mm and 8 mm. The tablet according to claim 1 or 2, characterized in that it contains coated or uncoated minigranules, microcapsules, nanoparticles or nanocapsules. Directly compressing the mixture of prepared components to form a bioadhesive layer, and Direct compression of the mixture of ingredients prepared to form the active ingredient layer; Or directly squeezing the mixture of the prepared products to form a barrier layer, or both, or squeezing one or both of the mixtures obtained by wet granulation. The manufacturing method of the tablet of Claim 1 or 2 characterized by including. The method according to claim 1 or 2, for oral, lingual, vaginal, anal, nasal, rectal route, or via the gastrointestinal tract for use in medicine, treatment, prophylaxis or health use in humans or animals. Tablets characterized in that they are prepared for use on internal organs by surgery. The method of claim 3, further comprising: one or more excipients which enable to improve bioadhesion; Or adjuvants that act as medicaments that are water soluble or have hydrophilic properties; Or a tablet characterized in that it contains a mixture of both. The excipient of claim 22 used in admixture with a bioadhesive material improves bioadhesion and can be used in combination with guar gum, xanthan gum, carob, carrageenate, pectin, alone or of biological or synthetic origin. Biological or synthetic proteins used in admixture with other proteins, cyclodextrins and betacyclodextrins, hydroxypropylbetacyclodextrins, inducers such as some methylated betacyclodextrins, acrylic acid crosslinked with divinyl glycol and calcium salts thereof Tablet characterized in that it contains an acrylic acid derivative. 23. The excipient of the hydrocellulose group such as lactose, mannitol, colloidal silicon dioxide, microcrystalline cellulose, excipient of the gelatin, cellulose ether group, polyethylene glycol (PEG), a polyoxamer, and a tablet characterized in that it is selected from pyrulidone. 23. The adjuvant of claim 22, wherein the adjuvant acts as a medicament with insoluble or hydrophobic properties, specifically hydrogenated castor oil, magnesium stearate, sky and synthetic oils, natural or semisynthetic waxes, fatty acid esters and polyoxyethylene esters, fatty acids And their derivatives such as fatty acid esters (monoglycerides and triglycerides) and polyethoxylated fatty acids (PEG stearate), fatty alcohols and fatty alcohol esters and polyethoxylated fatty alcohols (octyldodeces-25) Tablets characterized in that they are selected from their derivatives, and polyvinyl chloride.